Recent studies suggest that the steroid hormones estrogen and progesterone, their metabolic products, and chemical derivatives mediate protection against cellular damage and death. In a variety of organs and cell types, this has been documented for both acute insults and degenerative diseases. Among the protective mechanisms that are triggered by these steroid hormones is the re-establishment of the cytosolic free calcium ion homeostasis. This important gatekeeper of cellular decisions to progress towards differentiation, mitosis or apoptosis is critically dependent on the activity of intracellular calcium channels (ICC), inositol 1, 4, 5-trisphosphate receptor (IP3R) and ryanodine receptors (RyR). Intracellular calcium signaling mediated by these channels can be specifically altered by acute and chronic application of estrogen and/or progesterone. The present application will test the hypothesis that steroid hormones regulate intracellular calcium signaling through ICC that are important for neuronal function and viability. In particular, the effect of estrogen, progesterone, and related compounds, will be evaluated for their ability to induce posttranslational modifications of ICC and thereby elicit neuroprotection-related signaling pathways by controlling the cytosolic free calcium ion homeostasis. This is of high significance due to the fact that the non-genomic effects of estrogen and progesterone, which include intracellular calcium signaling, have the potential to provide the necessary information to design physiologically and clinically relevant cytoprotection strategies relevant for age-related disorders affecting the nervous systems and neurodegenerative diseases including Alzheimer's disease (AD). The overall goal of the study is to identify novel signaling pathways that are part of nongenomic actions of estrogen and progesterone in the nervous system. This identification of novel therapeutic targets will subsequently enable us to develop new strategies in cytoprotection for pathophysiological processes affecting neurons during aging and AD. AD is affecting the health and quality of life of an increasing number of individuals. In addition, changes in hormone levels in the aging population contribute as risk factors to AD and other age-related diseases. The present proposal addresses these pressing health issues that are also the focus of agency-wide NIH / NIA activities. Results from the proposed study will enable researchers to generate more effective drugs for AD and related diseases and clinicians to utilize more effective therapeutic approaches in hormone replacement therapy and in age related diseases including AD.